The main goal of this project is to examine sex differences in nicotine and cocaine-seeking behavior, and to examine the hypothesis that medications that reduce impulsivity would reduce these forms of drug seeking. Progesterone (PRO) is of interest because it reduces several forms of impulsivity (Llaneza and Frye 2008), and PRO will also be tested in combination with and compared with other drugs, such as varenicline (VAR) and atomoxetine (ATO) that reduce impulsivity and also reduce drug seeking in rats, and smoking relapse and cocaine relapse, respectively in humans. In addition, VAR and ATO will be compared and combined with PRO, and these single and combined treatments will be compared in male and female rats. A rat model of relapse will be used to compare these treatments and sex differences in Experiment 1, and two models of impulsivity, impulsive choice and impaired inhibition, will be studied in Experiment 2. The goal of Experiment 3 is to examine in female rats endogenously high (pregnancy) and low (lactation) levels of PRO on nicotine and cocaine-maintained behavior by comparing pregnant and lactating females with males and nonpregnant females. This preclinical work with provide translational information for future studies with humans. Overall, the purpose of Project III is to examine parallels between the nicotine and PRO (Project 1) PRO and ATO, combined and alone on human cocaine abusers that smoke (Project 2). This translational approach will provide basic proof of concept information on how endogenous PRO influences impulsivity and drug seeking. An innovative aspect of the proposed work is that the hormonal and pharmacological manipulations will be chronically applied. RELEVANCE (See instructions): Despite much effort, there are not yet highly effective approved medications for the direct treatment of cocaine and nicotine dependence. This SCOR will carry out interdisciplinary and translational investigations to identify pharmacological interventions targeting behaviors impaired in nicotine and cocaine dependent subjects to enhance the effectiveness of existing behavioral treatments for addiction.